PROJECT SUMMARY: Compartmentalization of Cyclic Nucleotide Signaling in the Ventral Hippocampus After the age of 60, nearly all individuals experience some form of cognitive decline?particularly memory deficits?and no drugs are able to prevent or reverse this loss. Age-related cognitive impairment, even in absence of dementia, increases health care costs and risk for disability. Cognitive decline is not a uniform process, with variability in symptom severity observed across individuals and across cognitive domains. Associative long-term memories (aLTMs)?particularly those involving experiences with family and friends? are more susceptible to age-related cognitive decline than are recognition long-term memories (rLTMs) for reasons that are not well understood. The lack of knowledge of the molecular mechanisms that govern age- related decline slows the development of novel therapeutics. Phosphodiesterase 11A (PDE11A) is an enzyme that breaks down cAMP and cGMP, and PDE11A may be an important molecular mechanism for regulating social aLTMs. PDE11A is almost exclusively expressed in a small area of the brain called the ventral hippocampus, which is a brain region that is required for the proper storage of social aLTMs. We have shown that hippocampal PDE11A4 expression dramatically increases across the lifespan in mice, rats, and humans. This raises the question of whether this age-related increase reflects a breakdown in physiological control of the hippocampus or an attempt of the brain to protect itself. In preliminary studies, we have shown that mice that lack or express very little PDE11A are completely protected against age-related cognitive decline of social aLTMs. Based on these and other preliminary studies, we hypothesize that age-related increases in hippocampal PDE11A4 occur in a subcellular compartment-specific manner and impair social aLTM. Across the 3 aims, we take an integrative experimental approach by coupling in vivo genetic manipulations with in vivo behavioral tests as well as ex vivo molecular and biochemical endpoints. In Specific Aim 1, we will determine if preventing or reversing age- related increases in PDE11A4 can rescue age-related impairments in social aLTMs. In Specific Aim 2, we will identify the circuit, cell type, and subcellular compartment where age-related increases in PDE11A4 expression occur and identify the posttranslational modifications that drive these compartment-specific effects. In Specific Aim 3, we will define the signals that drive age-related increases in PDE11A4 expression. These innovative studies will provide much needed insight into the fundamental mechanisms of social memory as well as the function and regulation of PDE11A in the brain. Targeting PDE11A may be a way to selectively restore cyclic nucleotide signaling in a specific brain region that regulates social memories, without affecting signaling elsewhere. This may relieve social deficits without causing unwanted side effects.